Blood thinners made from the complex carbohydrate heparin have been routinely used in the U.S. since the 1930s to keep veins, arteries and lungs clear of potentially fatal clots and to reduce the amount of time that kidney failure patients spend on dialysis machines. These drugs are so popular that there is not enough heparin—the active pharmaceutical ingredient (primarily derived from pig intestines) that enables these blood thinners to stop or prevent blood from clotting during medical procedures and treatments—to meet the daily U.S. demand of 300,000-plus doses. To make up the difference, U.S. drug makers purchase the majority of the heparin used in their products from China.

It's unlikely that many patients considered the source of the drug until earlier this year, when doctors began reporting hundreds cases of severe side effects (including dangerously low blood pressure) attributed to contaminated batches at U.S. hospitals and clinics around the country. The U.S. Food and Drug Administration (FDA) has cited 81 deaths as a result of the contamination and continues to investigate whether the tainted meds were responsible for others.

The heparin contamination was particularly disturbing, because the contaminated blood thinners passed through several layers of supposed screening. When the tainted drugs were discovered, Baxter, the supplier of 50 percent of heparin in the U.S. market, recalled nearly all of its doses (purchased from SPL). The FDA, which had since December been investigating complaints related to heparin products, tapped the expertise of several groups of scientists to find the nature and the source of the contamination by March and has since been working to tighten its screening of heparin imports from China, which supplies 70 percent of the heparin used in blood thinners worldwide. (The European Union, the U.S., Canada and Brazil supply nearly all of the rest.) The agency's investigation and efforts to find more effective ways of detecting contaminants is ongoing.

In an effort to prevent future scares, scientists are trying to develop a safer, more effective synthetic form of heparin that could be made in U.S. labs, thereby negating the need for purchasing possibly contaminated ingredients from China or other countries lacking stiff safety regs. Robert Linhardt, a professor of biology, chemistry and chemical engineering at Rensselaer Polytechnic Institute in Troy, N.Y., in February received a phone call that validated his five-year quest to develop heparin in the lab. Linhardt says he listened intently as a Baxter researcher told him about a report of severe allergic reactions to heparin-based blood thinners in dialysis patients, including children. "I was then asked if I was available to help with discovering the cause of this contamination," he says. "I responded affirmatively and then asked if it were not simply a bacterial contamination in the [heparin] vial-filling process. When I was assured that this was one of the first things tested for and ruled out, I realized that this would be a very interesting investigation, and I was hooked."

The crisis begins

The Missouri Department of Health and Senior Services first notified the U.S. Centers for Disease Control and Prevention (CDC) of a potential heparin problem in early January. Alexis Elward, an internist specializing in infectious disease at Saint Louis Children's Hospital, had alerted the department that some of her pediatric dialysis patients had suffered serious allergic reactions (including angioedema, shortness of breath, nausea, vomiting, diarrhea and abdominal pain) and, in some cases, dangerously low blood pressure after they took heparin-based blood thinners (used to prevent clots when waste is being filtered from the blood of patients whose own kidneys are too damaged to perform the function).

U.S. health care facilities had been purchasing more than one million multiple-dose vials of heparin-based blood thinners monthly, half of which were made by Baxter. Most of the remaining heparin products used in the U.S. are distributed by American Health Packaging in Valley Forge, Pa; APP Pharmaceuticals, LLC, in Schaumburg, Ill.; B. Braun Medical, Inc., in Bethlehem, Pa.; Covidien (formerly Tyco Healthcare) in Mansfield, Mass.; Hospira, Inc., in Lake Forest, Ill.; and Medtronic, Inc. [[http://www.reuters.com/article/healthNews/idUSN0730155620080507]], in Minneapolis. American Health Packaging, B. Braun, Covidien and Medtronic recalled heparin-based products from March through May due to concerns that they might be contaminated. Baxter was the hardest hit: Physicians reported about 350 adverse events from Baxter's heparin products in January and February alone, compared with fewer than 100 reports in all of 2007, according to the FDA. APP increased its production capacity and has taken over as the major supplier of the U.S. market.

Most of the problems involved dialysis patients who had received high intravenous doses of a type of heparin (high molecular weight heparin) that thins the blood for about an hour while they are undergoing treatment. Another type—low molecular weight heparin—thins the blood for hours longer than the high molecular weight variety and is more likely to be used on patients staying in the hospital (to prevent clots while bedridden). There are some synthetic forms of low molecular weight heparin, such as sanofi–aventis's Lovenox, but currently there is no synthetic high molecular weight alternative on the market.

Baxter had called Linhardt to tap his expertise and to help track down the source of contamination. He agreed to share his findings with FDA officials, who soon began calling him for daily updates and to get his take on what they found. "Often the FDA suggested experiments that I should try in my lab," he says. "Apparently, the FDA was using my lab to confirm and validate results that other laboratories were reporting."

On the trail of a killer

Within weeks, the FDA—working with Linhardt as well as research teams at the Massachusetts Institute of Technology (M.I.T.) and Washington University in St. Louis—had narrowed the list of suspected contaminants to oversulfated chondroitin sulfate (OSCS), because it mimics heparin's capabilities and appears to be heparin when tested in the lab. Although OSCS is based on chondroitin sulfate (prepared from animal cartilage or beef trachea) that many people take as an anti-inflammatory to treat osteoarthritis, OSCS has the opposite effect, activating immune system enzymes that cause inflammation as well as a drastic drops in blood pressure. The question: What was it doing in batches of heparin, where it would have no purpose other than to increase the volume, driving up sales of an artificially pumped up product, Linhardt says.

Baxter tracked the contaminant to SPL, which has a facility in China that manufactures the heparin that companies such as Baxter bought and used in their blood-thinner products. The Chinese facility, known as Changzhou SPL, used a supply chain for the ingredients to make its heparin that the included unregulated labs and farms in rural China. The FDA ultimately traced the poisoned heparin back to 12 Chinese companies that had added OSCS to their products.

Chinese officials initially disputed charges that the contaminants came from their country but have since acquiesced to the FDA's demand that Chinese companies test all ingredients used in U.S. drugs for contamination. The FDA, which says it has developed improved tests for screening heparin for contamination, is also planning to participate in an international summit at an undetermined location next year where international scientists and regulators will discuss ways to improve and enforce drug safety rules. This case—like those involving melamine in baby formula and pet food—illustrates the danger of U.S. dependence on products, including drugs, from other countries where safety standards are lower than those enforced by the FDA.

Jian Liu, an assistant professor of medicinal chemistry at the University of North Carolina School of Pharmacy at Chapel Hill agrees. "We don't like the way we're getting heparin now," says Liu, who is working with Linhardt to create synthetic heparin. "The process of getting the raw materials for heparin from swine leaves the finished product open to viral contamination."

The threat has given a new sense of urgency to Linhardt's effort to develop a synthetic version of the heparin use in short-term blood thinners, but he still faces some major obstacles. Although it is possible to bioengineer heparin in the lab, the drug's complex structure makes it difficult to mass produce: It takes at least 100 metric tons of heparin to meet the world's needs for a single year. Through trial and error, it took Linhardt and his team a year to make just 100 milligrams of his synthetic version. "The challenge is there are multiple enzymatic steps involved," Liu says. "These enzymes are very sensitive to temperature and not very stable," which means the fermentation process is not always successful.

Even if the enzymes survive the fermentation process and produce heparin, making that much of the drug synthetically (without the use of swine) could require using a 264,172-gallon (one-million-liter) fermenter 100 times. The largest fermenter on RPI's campus has a capacity of 10.6 gallons (40 liters) and would be able to produce only one gram of synthetic heparin at a time with each successful fermentation.

Linhardt hopes to be able to make a gram of synthetic heparin within a year, which would be enough to administer 100 doses in mice and allow the researchers to at least move forward with animal trials. He believes that one kilogram of synthetic heparin would provide the 10,000 doses needed to get through clinical testing on as many as 1,000 patients, although he says he is not able to give a timeline for when he would be able to make that much heparin. Success would mean that U.S. pharmaceutical companies could make the heparin they use in their blood-thinner products rather than importing it from China.

The heparin scare may prompt the U.S. National Institutes of Health to approve Linhardt's recent request for a $5-million federal grant over five years to complete his research. "Dr. Linhardt has a proof of concept," says Jawed Fareed, director the Special Coagulation Laboratory and the Hemostasis and Thrombosis Research Program at Loyola University Medical Center in Maywood, Ill. Fareed and Linhardt consulted during efforts to unravel the contamination mystery. Fareed became involved in the probe in March when doctors at the Medical Center's dialysis unit sought his advice on the FDA's heparin recall. "They wanted to know what they should do and asked if there was an alternative drug," he says. Fareed requested that the doctors send him all of the heparin in stock so he could determine whether they were contaminated in some way. Most of it was. "We were surprised by the results," he recalls, "and we were concerned about our patients."

A key factor in the success of synthetic heparin, at least initially: whether hospitals, clinics and insurance providers would be willing to pay a premium for it if it costs more than heparin coming from swine (which is about 20 cents per dose). Given how difficult it has been to produce small amounts today, it would take years and a "staggering" investment to make synthetic heparin a feasible business, says Erin Gardiner, a Baxter spokesperson, who adds that her company is not planning to get into the synthetic heparin business.

Still, Linhardt hopes that someone will take an interest in mass-producing the work he has begun. "The future is one that will be short continuously of heparin," he says. "Which means any adulterations of the heparin [imported by the U.S.], we're going to have to live with—or catch."